Process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid

a technology of trihydroxy-6-(((4ar, 10ar)7-hydroxy-1propyl) and manufacturing process, which is applied in the direction of drug composition, metabolic disorder, cardiovascular disorder, etc., can solve the problems of poor pharmacokinetic profile, inability to achieve clinical use of pd, and difficulty in predicting the conversion to the parent compound in humans

Active Publication Date: 2022-06-16
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0056]In addition to neurodegenerative diseases and disorders, other conditions in which an increase in dopaminergic turnover may be beneficial are in the improvement of mental functions including various aspects of cognition. It may also have a positive effect in depressed patients, and it may also be used in the treatment of obesity as an anorectic agent and in the treatment of drug addiction. It may improve minimal brain dysfunction (MBD), narcolepsy, attention deficit hyperactivity disorder and potentially the negative, the positive as well as the cognitive symptoms of schizophrenia.

Problems solved by technology

However, after several years of treatment (i.e. honeymoon period), complications arise due the inherent progression of the disease (i.e. sustained loss of dopaminergic neurons) as well as poor pharmacokinetic (PK) profile of L-DOPA.
However, these efforts are yet not in clinical use for the treatment of PD.
However, a known problem associated with the development of prodrugs for clinical use is the difficulties associated with predicting conversion to the parent compound in humans.

Method used

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  • Process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid
  • Process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid
  • Process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Compound (A2) (Step 1)

Example 1a

[0241]A 1 L three necked-flask was charged with 15 g (50.4 mmol, 1 eq.) HCl salt of compound (I), 450 ml dry dichloromethane, 40.4 ml (232 mmol) N,N-diisopropylethylamine (DIPEA) and 20.5 ml (96 mmol, 1.9 eq.) triisopropylsilyl chloride. The mixture was stirred at 20-25° C. under inert atmosphere. After 48 hours, the reaction mixture was cooled down to 0-5° C. and saturated NH4Cl solution was added (300 ml). The mixture was stirred for 10 minutes and then the phases were separated. The organic layer was washed with deionized water (2×150 ml), dried on Na2SO4 and evaporated, affording compound (A2) (27.8 g). Used directly in the next step (example 2a).

[0242]LC-MS (method A): retention time (RT)=2.71 min, [M+H]+=418.2 m / z.

example 1b

[0243]Into a 3 L three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed HCl salt of compound (I) (68 g, 228 mmol), dichloromethane (1.8 L), N,N-diisopropylethylamine (DIPEA) (83.6 g) and triisopropylsilyl chloride (135.7 g, 704.0 mmol). The resulting solution was stirred for 2 days at 25° C. The reaction was then quenched by the addition of 1000 mL of NH4Cl. The resulting solution was extracted with dichloromethane (2×1 L) and the organic layers combined and concentrated under vacuum. The residue was purified using silica gel column chromatography (eluent: ethyl acetate / petroleum ether (1:1)). This afforded compound (A2) (78 g) as an oil. Used directly in the next step (example 2b).

[0244]LC-MS (method B): RT=1.606 min, [M+H]+=418 m / z

[0245]1H NMR (CDC3, ppm): δ 6.64 (d, J=8.2 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 3.11 (dd, J=15.5, 5.0 Hz, 1H), 2.97 (dd, J=17.5, 5.0 Hz, 1H), 2.80-2.50 (m, 3H), 2.23 (dd, J=17.5, 11.5 Hz, 1H), 1.95 (d, J=13.0 H...

example 2

on of Compound (A3) (Step 2)

Example 2a

[0246]A 500 ml three-necked flask equipped with CaCl2 tube was charged with compound (A2) (8.7 g, 21 mmol), anhydrous dichloromethane (260 mL) and (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (20 g, 42 mmol). The solution was cooled down to 0-5° C. and boron trifluoride diethyl etherate (5.2 mL, 42 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice cold saturated solution of NaHCO3 (770 mL). After 10 minutes stirring the phases were separated and the aqueous phase was extracted with dichloromethane (235 mL). The combined organic phase was dried on Na2SO4 and evaporated to dryness to give 27.9 g crude product as an oil.

[0247]The crude material was purified by normal phase silica gel column chromatography affording compound (A3) (first experiment: 7.2 g, >90% purity (Quantitative HP...

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Abstract

The present invention relates to a process for manufacturing (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid with the formula (Id) below and pharmaceutically acceptable salts thereofThe compound of formula (Id) is a prodrug of a catecholamine for use in treatment of neurodegenerative diseases and disorders such as Parkinson's Disease.The invention also relates to a new intermediate of said process.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation application of U.S. application Ser. No. 16 / 876,843, filed May 18, 2020, which claims priority to Danish Application No. PA201900598, filed May 20, 2019. The entire contents of the aforementioned applications are hereby incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to a process for manufacturing (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid which is a compound for use in the treatment of neurodegenerative diseases and disorders such as Parkinson's Disease. The invention also relates to new intermediates of said process and the process of manufacturing said intermediates.BACKGROUND OF THE INVENTION[0003]Parkinson's disease (PD) is a common neurodegenerative disorder that becomes increasingly prevalent with age and affects an estimated seven to ten m...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H15/26
CPCC07H15/26C07H1/00A61P25/16A61P25/00A61P25/14A61P25/28A61P25/18A61P25/30A61P25/24A61P3/04A61P15/10A61P15/00A61P35/00A61P13/12A61P9/12C07H15/02C07H17/02A61K31/706
Inventor JUHL, MARTINKVÆRNØ, LISBETJACOBSEN, MIKKEL FOG
Owner H LUNDBECK AS
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